Background
Control and elimination strategies for trachoma, lymphatic filariasis, onchocerciasis,
schistosomiasis, ascariasis, trichuriasis and hookworm infection have striking similarities,
including the use of periodic mass drug administration (MDA). Because these diseases
tend to be co-endemic in the poorest communities of the poorest countries, such that
multiple NTDs are frequently found not just in the same populations but within the
same individuals [1], it has been suggested that mapping, treatment, impact monitoring,
and post-elimination surveillance could be coordinated to better utilise limited human
and financial resources. Although many programmes now distribute multiple anthelmintics
simultaneously, progress in integrating mapping [2], [3], [4], monitoring, and surveillance
[5] activities has been slow [6]. Ideally, population sampling strategies, fieldwork
protocols, and sample types (e.g., blood or urine) could all be harmonised between
diseases to increase population compliance, simplify overall survey procedures, and
decrease costs.
For each of these diseases, current diagnostic tools are imperfect (Table S1A), especially
for areas with low prevalence. A cost-effective strategy for improved tool development
would incorporate integration of diagnostic strategies from the outset [7], [8].
To review available methods for population-based assessment of NTDs, develop target
product profiles for tools to monitor infection burden, and consider how those tools
would be used in the context of disease elimination programmes, the London School
of Hygiene & Tropical Medicine (LSHTM), in collaboration with the World Health Organization,
held a consultation at LSHTM from July 19–20, 2010. Participants included disease
experts, laboratory and field scientists, authorities on diagnostics, control programme
managers, mathematical modellers, and health economists. By bringing together, for
the first time, individuals with such a broad spectrum of intersecting disease- and
discipline-specific interests to consider issues surrounding integration of diagnostic
systems, the consultation aimed to improve on the usual vertical approach to tropical
diseases research, encouraging formulation of an innovative approach.
This article summarises that consultation's outcomes, suggests target product profiles
and a list of immediate research priorities, and drafts a road map for future efforts.
We argue for development of a multiplex platform for NTD mapping, monitoring, and
surveillance, and suggest changes to policy that might ensue if such a system were
to become available.
Evolution of Diagnostic Needs with Successful Programme Implementation
We conceptualise four time points or periods at which disease elimination programmes
require diagnostics:
Mapping to establish baseline disease prevalence, facilitating targeting of interventions.
Impact monitoring after interventions have commenced.
The stopping decision, which determines whether the pre-defined elimination target
has been reached, allowing discontinuation of interventions.
Post-elimination surveillance after intervention has ceased.
Mapping and impact monitoring may require both qualitative and quantitative data from
each individual sampled, in order to generate information about the prevalence and
intensity of infection. As the prevalence falls with successful control interventions,
the intensity of infection also falls. Therefore, to detect the last remaining infections,
a more sensitive test may be required. However, for some NTDs (e.g., trachoma), individuals
with a low pathogen load are unlikely to transmit infection, so sensitivity is less
important. Specificity becomes more important as disease prevalence decreases and
is an absolute requirement in certifying elimination [5].
To enable meaningful interpretation of the effect of interventions, the sensitivity
and specificity of diagnostic tools used in mapping should be about the same as the
sensitivity and specificity of tools used in impact monitoring. One rational difference
between mapping and impact monitoring may be the commissioning (in environments where
high baseline infection prevalence is expected) of mapping surveys enrolling the same
number of clusters over a larger area, in order to save resources. For example, province-
or region-level baseline assessments of trachoma prevalence are now accepted for the
purposes of requesting donated azithromycin in areas where active trachoma prevalence
in 1–9-year-olds is expected (and then proven) to be higher than 10%; subsequent impact
monitoring is performed at district level.
Ideally, stopping decisions would be based on documentation of the absence of transmission.
In practice, however, these decisions are often made once there is documentation of
absence of current or previous infection in a sentinel population, such as children
born after the time transmission is believed to have been interrupted [9]. Stopping
decisions require data generated using diagnostic tools whose specificity is at least
as high as those used for mapping, to avoid unnecessarily prolonging MDA. Tool sensitivity
is also crucial here to avoid premature MDA cessation and later rebound in infection
prevalence. An assay considered adequate for mapping when prevalence is high may have
inadequate sensitivity to detect infection in areas with low infection intensity.
Stopping decisions are made during the process of impact monitoring, and also mark
the commencement of post-elimination surveillance. Data generated to inform stopping
decisions should therefore provide useful comparators against both impact monitoring
data and data that will subsequently be collected as part of surveillance activities.
In general, programmes are likely to require antigen- or nucleic acid–detection assays
(to determine prevalence of current infection) for mapping and impact monitoring prior
to elimination, and a combination of assays detecting antigens (or nucleic acid) and
antibodies (to assess prevalence of exposure in particular population subsets) for
post-elimination surveillance. For the worm infections, reliance on detection of transmission
stages (eggs, microfilariae) becomes more problematic as the elimination endpoint
is approached, since (other than for ascariasis) this will only identify hosts infected
with both male and female adults. Specific detection of IgG subtypes may be useful
in some cases, particularly if applied at population level: for example, IgG4 responses
are characteristic of chronic helminth infections, and titres decline following successful
therapy in lymphatic filariasis, onchocerciasis, schistosomiasis, and strongyloidiasis.
Monitoring vector, intermediate host, or non-human reservoir [10] populations for
the presence of parasites may be important in confirming elimination of infection.
Apart from performance characteristics, it is important to consider the operational
characteristics of an assay. Large population-based surveys may require tests that
can be batched for high throughput. Point of care tests, which generally detect antigen
or antibody in dipstick or card format, are relatively cheap, require little formal
operator training, and can be performed in the community [11]. They are of particular
use when programme personnel need to make immediate decisions as to whether intervention
is required. This is helpful when individual patients are being assessed. However,
for MDA, where decisions are needed on whether or not to treat whole communities or
districts, laboratory-based tests are probably adequate, provided samples are easy
to collect (e.g., fingerprick) and transport (e.g., dried blood spots).
Target Product Profiles and Immediate Research Priorities
Target product profiles for lymphatic filariasis, trachoma, schistosomiasis, onchocerciasis,
and soil-transmitted helminths are shown for the mapping and impact monitoring phases
in Table 1, and for the post-elimination surveillance phase (first four diseases only)
in Table 2. The tables consider only the needs for diagnostic tools in mapping, monitoring,
and surveillance of human infection because we see these as priorities for any first-generation
integrated platform for NTD diagnostics; we have, for the moment, put aside programme
requirements for monitoring MDA coverage; measures of morbidity; possible emergence
of drug resistance; prevalence of infection in vectors, intermediate hosts, or reservoir
animals; and force of transmission through environmental sampling.
10.1371/journal.pntd.0001746.t001
Table 1
Proposed target product profiles for diagnostic tools for selected NTDs, mapping,
and impact monitoring.
Characteristic
Lymphatic Filariasis
Trachoma
Schistosomiasis
Onchocerciasis
Soil-Transmitted Helminths
Intended use
Mapping, monitoring, and stopping decision
Mapping, monitoring, and stopping decision
Mapping, monitoring, and stopping decision
Mapping, monitoring, and stopping decision
Mapping and monitoring
Possible target populationa
6–15-year-old children
1–9-year-old children (could be adjusted)
6–15-year-old children plus occupational groups
6–15-year-old children
6–15-year-old children
Possible sample types
Blood spot
Eye swab (other: mouth or nose swab, tears)
Blood spot or urine (avoid stool if possible)
Blood spot
Blood spot or urine (avoid stool if possible)
Ideal diagnostic marker
Parasite antigen
C. trachomatis antigen
Species-specific antigen OR pan-genus antigen
Parasite antigen
Parasite antigen
Ideal test format
POC or high throughput laboratory assay
POC or high throughput laboratory assay
POC assay
POC or high throughput laboratory assay
POC assay
Availability of ideal diagnostic marker
Available but not right format, low reliability, high cost, and temperature sensitive
Available but not right format
Not yet available
Not yet available. IgG4 antibody may be a reasonable proxy
Not yet available
Required performance characteristics
95% sensitive; W. bancrofti-specific
>50% sensitive, 99.5% specific
>50% sensitive, 99.5% specific
>50% sensitive, 99.5% specific
>50% sensitive, 99.5% specific
Comparator assay (current reference standard)
Night blood micro-filaraemia
Quantitative PCR
Kato-Katz (multiple slides and multiple days) and/or urine filtration
Skin snips to detect micro-filariae
Kato-Katz (multiple slides and multiple days)
Possible sampling strategies
PBPS/LQAS, school based, sentinel sites
PBPS/LQAS, home based, sentinel sites
PBPS/LQAS, school based, 50/school, increasing with control
PBPS/LQAS
PBPS/LQAS, school based
LQAS, lot quality assurance sampling; NTDs, neglected tropical diseases; PBPS, population-based
prevalence survey; PCR, polymerase chain reaction; POC, point of care.
a
Based on peak infection prevalence, convenience, or both.
10.1371/journal.pntd.0001746.t002
Table 2
Proposed target product profiles for diagnostic tools for selected NTDs, post-elimination
surveillance.a
Characteristic
Lymphatic Filariasis
Trachoma
Schistosomiasis
Onchocerciasis
Intended use
Post-elimination incidence of infection
Post-elimination incidence of infection
Post-elimination incidence of infection
Post-elimination incidence of infection
Possible target population
Children born after transmission interruption
Children born after transmission interruption
Children born after transmission interruption
Children born after transmission interruption
Possible sample types
Blood spot
Blood spot
Blood spot or urine (avoid stool if possible)
Blood spot
Ideal diagnostic marker
Antibody
Antibody to a conserved species-specific epitope of MOMP
Antibody
Ov16 antibody
Availability of ideal diagnostic marker
Not available
Libraries available
In development
Available, but additional validation needed
Ideal test format
High throughput laboratory assay
High throughput laboratory assay
High throughput laboratory assay
High throughput laboratory assay
Population infection thresholds (for stopping MDA)
1%
Not defined
10% of school-aged children
1/3,000
Probable sampling strategy
PBPS
PBPS
PBPS or school surveys (or sentinel occupations)
PBPS
a
Schistosomiasis is included in this table because several countries have programmes
to eliminate this disease [18], [19]. The soil-transmitted helminth infections are
not included because (as for schistosomiasis in most endemic states) the current goal
is prevention of morbidity in school-aged children through periodic high-coverage
MDA.
ICT, immunochromatographic card test; LF, lymphatic filariasis; MDA, mass drug administration;
MOMP, major outer membrane protein of C. trachomatis; NTDs, neglected tropical diseases;
PBPS, population-based prevalence survey.
The target product profiles that we set out here are aspirational. Some tests (e.g.,
antigen assay for W. bancrofti [Table 1] or Ov16 antibody assay in previously onchocerciasis-endemic
areas [Table 2]) appear close to being validated for programme use, while for others,
numerous technical hurdles remain. For this reason, we expect some of our target product
profiles—particularly blood- or urine-based antigen detection tests for the soil-transmitted
helminthiases—to be controversial. However, there is presently at least one commercially
available ELISA kit to detect IgG directed against Ascaris lumbricoides in human serum:
it should be possible to develop a test to detect the antigen driving that antibody
response. If such antigens only circulate briefly in the early part of the Ascaris
life cycle, this may actually be helpful in interpreting test results at community
level, since antigen detection will indicate the presence of ongoing transmission.
Immediate research priorities are shown in Table 3.
10.1371/journal.pntd.0001746.t003
Table 3
Immediate research priorities.
Disease
Research Goal
Feasibility (0–10a: 0, Impossible; 10, Inevitable)
Impact if Achieved (0–10a: 0, None; 10, Massive)
Lymphatic filariasis
Development of antigen tests to usable/reliable format
9
8 if ≤USD 0.50
Development and validation of tests (e.g., IgG4-subclass antibody detection tests
using recombinant Bm14, BmR1, WbSXP, and W. bancrofti-specific antigens [20] or PCR-based
detection of parasite DNA in homogenised mosquitoes [21]) useful for post-elimination
surveillance, with accompanying standardised survey methodologies
9
8 if ≤USD 0.50
Trachoma
Development of a test for ocular C. trachomatis infection [22] able to maintain specificity
at high temperatures and low humidity [23]
9
8 if ≤USD 0.50
Development of eye/nose swab-, saliva-, or blood-based anti-C. trachomatis antibody
test and exploration of the impact of successful trachoma control on antibody profiles
in endemic populations
3
5
Development and validation of a school-based survey protocol (need threshold minimum
school attendance)
7
8
Schistosomiasis
Development of antigen [24] or antibody [25] isotype combination(s) useful in high
and low transmission intensity environments, able to distinguish current from past
infection
8
9
Development of antigen or antibody isotype combination(s) to distinguish between different
species
8
4
Development of serum markers of morbidity
6
8
Soil-transmitted helminthiases
Development of reliable blood- or urine-based assays for detection of current infection
4
9
Development of serum markers of morbidity
6
8
Onchocerciasis
Development of a quantitative antigen test for use in endemic areas in Africa and
validation of Ov16 antibody test for demonstrating interruption of transmission in
Africa
5
8
Development of a test for loaiasis
5
9
a
Determined by expert consensus.
Discussion
Trachoma, lymphatic filariasis, schistosomiasis, onchocerciasis, and soil-transmitted
helminth infections are found in overlapping populations; are controlled through broadly
similar, often complementary, strategies involving MDA; and are mapped and monitored
by sampling individuals from the population-at-risk using strategies that are also
broadly similar but different in detail. Programmes for their control and elimination
require improved diagnostic tools to guide decisions on the required intensity, frequency,
and duration of intervention and to conduct surveillance for re-emergence of infection
after elimination. Similarities between target product profiles (Tables 1 and 2) suggest
the feasibility and desirability of integration of diagnostic approaches.
In many areas in which NTDs are highly endemic, basic health infrastructure is sparse
or non-existent, and there are few trained personnel. Local laboratories may not have
access to refrigeration, reliable power, or piped water; have highly variable capacity
for performing diagnostic assays; and the capacity they do have is in general insufficient
to meet existing diagnostic requirements of local clinical services. They are therefore
ill-equipped to take on the extra burden of generating data to feed into NTD elimination
programmes without provision of additional money, staff, training, equipment, reagents,
and utilities—or robust technologies that could perform well despite limitations to
supply of these resources.
The ideal integrated system might therefore be a portable, self-contained diagnostics
platform, capable of performing multiplex assays for several infections of interest
on one or a small number of sample types. A system employing microfluidics (“lab-on-a-chip”)
[12], [13], [14] technology could fulfil these requirements. The platform should be
able to simultaneously undertake multiple roles in different NTD control programmes,
each of which might be at various points of evolution within a given population. For
example, in a district that had been hyperendemic at baseline for trachoma, soil-transmitted
helminths, and lymphatic filariasis but in which interventions had already been in
progress for a number of years, the platform would be capable of accurately detecting
reductions in ocular C. trachomatis infection, whilst simultaneously measuring the
prevalence of soil-transmitted helminth infection and monitoring for post-elimination
re-emergence of lymphatic filariasis. Since diseases of potential interest will vary
from one population to the next, a modular format would provide opportunities to swap
diagnostic capacity for particular infections in and out of the platform according
to global, regional, or local priority. For example, in onchocerciasis-endemic areas,
the capacity to test for loaiasis at the same time as measuring the prevalence of
O. volvulus infection would benefit programmes [15]. Equally, the platform should
be adaptable for the assessment of the community prevalence of HIV infection, malaria
parasitaemia or anti-malaria antibody, and/or seroprevalence of antibodies to measles,
rubella, or hepatitis B surface antigen following vaccination campaigns.
Our vision can be conceptualised as the delivery of two linked components: a hardware
module, on which samples will be processed, and various elements of software, including
both the assays themselves and the algorithms to guide their use in the field. To
ensure that any new technologies are ready for both registration and end use, field
personnel, programme managers, regulatory agencies, ministries of health, and other
key stakeholders should be involved in platform development and evaluation.
In addition to the potential savings to existing vertical control programmes that
would become possible through integration of diagnostic tools, this approach has several
other potential advantages.
First, it makes conducting surveys to rule out specific diseases easier and more cost-effective.
This can occasionally yield surprising results. In Burundi in 2007, examination for
trachoma was included alongside fieldwork conducted nationally to estimate the prevalences
of schistosomiasis and soil-transmitted helminths, in order to confirm the long-held
belief that Burundi was trachoma-free. Active trachoma was found in children throughout
the country, and trachoma control activities including azithromycin MDA commenced
in 2011 in three districts.
Second, proof-of-concept of an integrated diagnostics platform could facilitate programme
planning for other infections for which control strategies are in the early stages
of development. An October 2009 WHO expert consultation discussed recent work piloting
taeniasis elimination in Peru and possible MDA approaches for food-borne trematode
infections. These diseases may have global control initiatives developed in the foreseeable
future.
Third, establishing capacity for reliable diagnosis of what have hitherto been the
most neglected diseases could catalyse a frame-shift in the global health community's
vision of developing world laboratory science. A diagnostics platform that could be
configured to generate community- or individual-level data for any of the infections
already mentioned as well as perform tests for (for example) sexually transmitted
infections, human African trypanosomiasis, or leishmaniasis would represent a game-changing
advance in the fight against infectious diseases.
World Health Assembly Resolution 60.29 on Health Technologies recognizes that medical
devices are indispensable tools for prevention, diagnosis, treatment, and rehabilitation
in health care [16]. It is widely accepted that the availability of, and access to,
appropriate and affordable health technologies in low- and middle-income countries
remain inadequate. In 2010, WHO held the first Global Forum on Medical Devices [17],
which featured selected technological innovations that could improve global health.
The innovators identified financing, manufacturing partners, and distribution channels
as their top three challenges in getting their technologies into resource-limited
settings. WHO undertook to continue to interact with industry, funding agencies, academia,
and international organizations to raise awareness of the need to design, produce,
and commercialize innovative, accessible, and robust technologies which address the
needs of health systems particularly in low-resource settings. The development, evaluation,
and deployment of an integrated platform to monitor progress towards NTD elimination
would be consistent with this WHO vision.
Supporting Information
Table S1
Performance against the ASSURED criteria [11] of existing diagnostic tools for the
neglected tropical diseases employing mass drug administration.
(DOC)
Click here for additional data file.